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  • Review Article
  • Published:

Rituximab therapy in nephrotic syndrome: implications for patients' management

Nature Reviews Nephrology volume 9, pages 154–169 (2013)Cite this article

Subjects

Abstract

Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. The best outcomes are seen in patients with steroid-dependent nephrotic syndrome who have failed to respond to multiple therapies. By contrast, the benefits of rituximab therapy are limited in patients with steroid-resistant nephrotic syndrome, particularly those with focal segmental glomerulosclerosis (FSGS). Therapy with plasma exchange and one or two doses of rituximab has shown success in patients with recurrent FSGS. Young patients and those with normal serum albumin at recurrence of nephrotic syndrome are most likely to respond to rituximab therapy. A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A2 receptor autoantibodies, which are implicated in the pathogenesis of this disorder. Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. However, the available evidence of efficacy of rituximab therapy is derived chiefly from small case series and requires confirmation in prospective, randomized, controlled studies that define the indications for use and predictors of response to this therapy.

Key Points

  • Therapy with rituximab induces and maintains remission effectively in patients with difficult-to-treat, steroid-dependent nephrotic syndrome; sustained remission enables the reduction of steroid doses and withdrawal of calcineurin inhibitors

  • In patients with steroid-resistant nephrotic syndrome who fail to respond to treatment with calcineurin inhibitors, the response to rituximab therapy is less efficacious

  • Rituximab dose(s), the rate of B-cell recovery and clinical response are not closely correlated

  • Combined therapy with rituximab and plasma exchange might be useful to prevent or treat recurrence of focal segmental glomerulosclerosis

  • Therapy with rituximab should be considered in patients with idiopathic membranous nephropathy who fail to respond to treatment with cyclophosphamide or calcineurin inhibitors

  • Acute infusion reactions are frequent but transient in patients who receive rituximab; serious adverse effects, including an increased risk of infections, are uncommon

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Figure 1: Proposed mechanisms of action of rituximab in patients with nephrotic syndrome.
Figure 2: Rates of remission after rituximab therapy.

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References

  1. Amoroso, A. et al. Understanding rituximab function and resistance: implications for tailored therapy. Front. Biosci. 16, 770–782 (2011).

    Article  CAS  Google Scholar 

  2. Ejaz, A. A., Asmar, A., Alsabbagh, M. M. & Ahsan, N. Rituximab in immunologic glomerular diseases. mAbs 4, 198–207 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  3. US Food and Drug Administration. News and events [online], (2012).

  4. Iijima, K. Rituximab for childhood refractory nephrotic syndrome. Pediatr. Int. 53, 617–621 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Takei, T. & Nitta, K. Rituximab and minimal change nephrotic syndrome: a therapeutic option. Clin. Exp. Nephrol. 15, 641–647 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Araya, C. E. & Dharnidharka, V. R. The factors that may predict response to rituximab therapy in recurrent focal segmental glomerulosclerosis: a systematic review. J. Transplant. http://dx.doi.org/10.1155/2011/374213.

  7. Appel, G. B. Rituximab in membranous nephropathy: is it a first-line treatment? J. Am. Soc. Nephrol. 23, 1280–1282 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Kidney Disease Improving Global Outcomes (KDIGO). General principles in the management of glomerular disease. Kidney Int. Suppl. 2, 156–162 (2012).

  9. Gulati, A. et al. Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome. Kidney Int. 82, 1130–1135 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Troyanov, S. et al. Idiopathic membranous nephropathy: definition and relevance of a partial remission. Kidney Int. 66, 1199–1205 (2004).

    Article  PubMed  Google Scholar 

  11. Cragg, M. S., Walshe, C. A., Ivanov, A. O. & Glennie, M. J. The biology of CD20 and its potential as a target for mAb therapy. Curr. Dir. Autoimmun. 8, 140–174 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Hofmeister, J. K., Cooney, D. & Coggeshall, K. M. Clustered CD20 induced apoptosis: src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx and caspase 3-dependent apoptosis. Blood Cells Mol. Dis. 26, 133–143 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Cartron, G., Watier, H., Golay, J. & Solal-Celigny, P. From the bench to the bedside: ways to improve rituximab efficacy. Blood 104, 2635–2642 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Semac, I. et al. Anti-CD20 therapeutic antibody rituximab modifies the functional organization of rafts/microdomains of B lymphoma cells. Cancer Res. 63, 534–540 (2003).

    CAS  PubMed  Google Scholar 

  15. Koyama, A., Fujisaki, M., Kobayashi, M., Igarashi, M. & Narita, M. A glomerular permeability factor produced by human T cell hybridomas. Kidney Int. 40, 453–460 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Vallerskog, T. et al. Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with, S.L.E. Clin. Immunol. 122, 62–74 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Stasi, R. et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 112, 1147–1150 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Vigna-Perez, M. et al. Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res. Ther. 8, R83 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sfikakis, P. P. et al. Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin. Immunol. 123, 66–73 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Saadoun, D. et al. Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 111, 5334–5341 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Sfikakis, P. P. et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand. Arthritis Rheum. 52, 501–513 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Tokunaga, M. et al. Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab. Rheumatology (Oxford) 44, 176–182 (2005).

    Article  CAS  Google Scholar 

  23. Hu, C. Y. et al. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J. Clin. Invest. 117, 3857–3867 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Araya, C. et al. T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr. Nephrol. 24, 1691–1698 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Le Berre, L. et al. Induction of T regulatory cells attenuates idiopathic nephrotic syndrome. J. Am. Soc. Nephrol. 20, 57–67 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shao, X. S. et al. The prevalence of TH17 cells and FOXP3 regulate T cells (Treg) in children with primary nephrotic syndrome. Pediatr. Nephrol. 24, 1683–1690 (2009).

    Article  PubMed  Google Scholar 

  27. Wang, L., Li, Q., Wang, L. J. & Li, X. Level of TH17 cell and CD4+; CD25+; Foxp3+; regulatory T cells in peripheral blood mononuclear cells of primary nephrotic syndrome in children [Chinese]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 26, 783–786 (2010).

    CAS  PubMed  Google Scholar 

  28. Bertelli, R. et al. Failure of regulation results in an amplified oxidation burst by neutrophils in children with primary nephrotic syndrome. Clin. Exp. Immunol. 161, 151–158 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Shimada, M. et al. Minimal change disease: a “two-hit” podocyte immune disorder? Pediatr. Nephrol. 26, 645–649 (2011).

    Article  PubMed  Google Scholar 

  30. Fervenza, F. C. et al. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin. J. Am. Soc. Nephrol. 5, 2188–2198 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yeo, W. S. et al. Effect of rituximab on T-cell subsets in nephrotic children with focal segmental glomerulosclerosis (FSGS) [abstract F-PO1277]. J. Am. Soc. Nephrol. 21, 403 (2010).

    Google Scholar 

  32. Lin, C. Y. Immune modulatory mechanism of rituximab in steroid refractory heavy proteinuria [abstract SA-PO377]. J. Am. Soc. Nephrol. 23, 724 (2012).

    Google Scholar 

  33. Perosa, F., Favoino, E., Caragnano, M. A. & Dammacco, F. Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor. Blood 107, 1070–1077 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Bezombes, C. et al. Rituximab antiproliferative effect in B lymphoma cells is associated with acid-sphingomyelinase activation in raft microdomains. Blood 104, 1166–1173 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Fornoni, A. et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci. Transl. Med. 3, 85–95 (2011).

    Article  CAS  Google Scholar 

  36. Tan, R. et al. Nef interaction with actin compromises human podocyte actin cytoskeletal integrity. Exp. Mol. Pathol. 94, 51–57 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chan, C. Y., Yeo, W. S., Wei, C., Biswas, S. K. & Yap, H. K. High suPAR levels in FSGS patients is associated with decreased TREG cells [abstract FR-PO483]. J. Am. Soc. Nephrol. 23, 484 (2012).

    Article  CAS  Google Scholar 

  39. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  40. Liu, L. L. et al. TH17/TREG imbalance in adult patients with minimal change nephrotic syndrome. Clin. Immunol. 139, 314–320 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Ng, C. M., Bruno, R., Combs, D. & Davies, B. Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. J. Clin. Pharmacol. 45, 792–801 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Breedveld, F. et al. Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response. J. Clin. Pharmacol. 47, 1119–1128 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Berinstein, N. L. et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Ann. Oncol. 9, 995–1001 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Kamei, K. et al. Single dose of rituximab for refractory steroid-dependent nephrotic syndrome in children. Pediatr. Nephrol. 24, 1321–1328 (2009).

    Article  PubMed  Google Scholar 

  45. Fervenza, F. C. et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 73, 117–125 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Regazzi, M. B. et al. Pharmacokinetic behavior of rituximab: a study of different schedules of administration for heterogenous clinical settings. Ther. Drug Monit. 27, 785–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Fujinaga, S. et al. Single infusion of rituximab for persistent steroid-dependent minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr. Nephrol. 25, 539–544 (2010).

    Article  PubMed  Google Scholar 

  48. Guigonis, V. et al. Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr. Nephrol. 23, 1269–1279 (2008).

    Article  PubMed  Google Scholar 

  49. Sellier-Leclerc, A. L. et al. Rituximab efficiency in children with steroid-dependent nephrotic syndrome. Pediatr. Nephrol. 25, 1109–1115 (2010).

    Article  PubMed  Google Scholar 

  50. Ito, S. et al. Survey of rituximab treatment for childhood-onset refractory nephrotic syndrome. Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467-012-2319-1.

  51. Sellier-Leclerc, A. L. et al. Rituximab in steroid dependent idiopathic nephrotic syndrome in childhood: follow-up after CD19 recovery. Nephrol. Dial. Transplant. 27, 1083–1089 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Gulati, A. et al. Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report. Clin. J. Am. Soc. Nephrol. 5, 2207–2212 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hoxha, E., Stahl, R. A. & Harendza, S. Rituximab in adult patients with immunosuppressive-dependent minimal change disease. Clin. Nephrol. 76, 151–158 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Prytula, A. et al. Rituximab in refractory nephrotic syndrome. Pediatr. Nephrol. 25, 461–468 (2010).

    Article  PubMed  Google Scholar 

  55. Kemper, M. J. et al. Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol. Dial. Transplant. 27, 1910–1915 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Bagga, A. & Mantan, M. Nephrotic syndrome in children. Indian J. Med. Res. 122, 13–28 (2005).

    PubMed  Google Scholar 

  57. Kidney Disease Improving Global Outcomes (KDIGO). Steroid-sensitive nephrotic syndrome in children. Kidney Int. Suppl. 2, 163–171 (2012).

  58. Hodson, E. M., Willis, N. S. & Craig, J. C. Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD002290. http://dx.doi.org/10.1002/14651858.CD002290.pub3.

  59. Ishikura, K. et al. Effective and safe treatment with cyclosporine in nephrotic children: a prospective, randomized multicenter trial. Kidney Int. 73, 1167–1173 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Benz, K., Dötsch, J., Rascher, W. & Stachel, D. Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr. Nephrol. 19, 794–797 (2004).

    Article  PubMed  Google Scholar 

  61. Sugiura, H. et al. Effect of single-dose rituximab on primary glomerular diseases. Nephron Clin. Pract. 117, c98–c105 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Kisner, T., Burst, V., Teschner, S., Benzing, T. & Kurschat, C. E. Rituximab treatment for adults with refractory nephrotic syndrome: a single-center experience and review of the literature. Nephron Clin. Pract. 120, c79–c85 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Ochi, A. et al. Rituximab treatment for adult patients with focal segmental glomerulosclerosis. Intern. Med. 51, 759–762 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Sinha, A., Bhatia, D., Gulati, A., Hari, P. & Bagga, A. Efficacy and safety of rituximab in difficult steroid resistant & dependent nephrotic syndrome [abstract OP64]. Pediatr. Nephrol. 27, 1605–1829 (2012).

    Article  Google Scholar 

  65. Ravani, P. et al. Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial. Clin. J. Am. Soc. Nephrol. 6, 1308–1315 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Magnasco, A. et al. Rituximab in children with resistant idiopathic nephrotic syndrome. J. Am. Soc. Nephrol. 23, 1117–1124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ito, S. et al. Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome. Pediatr. Nephrol. 26, 1823–1828 (2011).

    Article  PubMed  Google Scholar 

  68. Sinha, A., Bagga, A., Gulati, A. & Hari, P. Short-term efficacy of rituximab versus tacrolimus in steroid-dependent nephrotic syndrome. Pediatr. Nephrol. 27, 235–241 (2012).

    Article  PubMed  Google Scholar 

  69. Ruggenenti, P. et al. Rituximab in steroid-dependent or multirelapsing nephrotic syndrome of adults and children: results from the NEMO trial [abstract SA-PO375]. J. Am. Soc. Nephrol. 23, 484 (2012).

    Google Scholar 

  70. Japan Medical Association for Clinical Trials. Double-Blind Study of IDEC-C2B8 in patients with childhood-onset refractory nephrotic syndrome. JMACCT Clinical Trials Registry [online], (2012).

  71. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  72. Bagga, A., Sinha, A. & Moudgil, A. Rituximab in patients with the steroid-resistant nephrotic syndrome. N. Engl. J. Med. 356, 2751–2752 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Kurosu, N. et al. Successful use of single-dose rituximab for the maintenance of remission in a patient with steroid-resistant nephrotic syndrome. Intern. Med. 48, 1901–1904 (2009).

    Article  PubMed  Google Scholar 

  74. Suri, M., Tran, K., Sharma, A. P., Filler, G. & Grimmer, J. Remission of steroid-resistant nephrotic syndrome due to focal and segmental glomerulosclerosis using rituximab. Int. Urol. Nephrol. 40, 807–810 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Nakayama, M. et al. Rituximab for refractory focal segmental glomerulosclerosis. Pediatr. Nephrol. 23, 481–485 (2008).

    Article  PubMed  Google Scholar 

  76. Peters, H. P., van de Kar, N. C. & Wetzels, J. F. Rituximab in minimal change nephropathy and focal segmental glomerulosclerosis: report of four cases and review of the literature. Neth. J. Med. 66, 408–415 (2008).

    CAS  PubMed  Google Scholar 

  77. Fernandez-Fresnedo, G. et al. Rituximab treatment of adult patients with steroid-resistant focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 4, 1317–1323 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kari, J. A. et al. Rituximab for refractory cases of childhood nephrotic syndrome. Pediatr. Nephrol. 26, 733–737 (2011).

    Article  PubMed  Google Scholar 

  79. Kong, W. Y., Swaminathan, R. & Irish, A. Our experience with rituximab therapy for adult-onset primary glomerulonephritis and review of literature. Int. Urol. Nephrol. http://dx.doi.org/10.1007/s11255-012-0206-0.

  80. Couser, W. Recurrent glomerulonephritis in the renal allograft: an update of selected areas. Exp. Clin. Transplant. 3, 283–288 (2005).

    PubMed  Google Scholar 

  81. Ponticelli, C. & Glassock, R. J. Posttransplant recurrence of primary glomerulonephritis. Clin. J. Am. Soc. Nephrol. 5, 2363–2372 (2010).

    Article  PubMed  Google Scholar 

  82. Vinai, M., Waber, P. & Seikaly, M. G. Recurrence of focal segmental glomerulosclerosis in renal allograft: an in-depth review. Pediatr. Transplant. 14, 314–325 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Weber, S. et al. NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int. 66, 571–579 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Baum, M. A. et al. Loss of living donor renal allograft survival advantage in children with focal segmental glomerulosclerosis. Kidney Int. 59, 328–333 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Cibrik, D. M., Kaplan, B., Campbell, D. A. & Meier-Kriesche, H. U. Renal allograft survival in transplant recipients with focal segmental glomerulosclerosis. Am. J. Transplant. 3, 64–67 (2003).

    Article  PubMed  Google Scholar 

  86. Hariharan, S. et al. Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR). Transplantation 68, 635–641 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Pardon, A. et al. Risk factors and outcome of focal and segmental glomerulosclerosis recurrence in adult renal transplant recipients. Nephrol. Dial. Transplant. 21, 1053–1059 (2006).

    Article  PubMed  Google Scholar 

  88. Newstead, C. G. Recurrent disease in renal transplants. Nephrol. Dial. Transplant. 18 (Suppl. 6), 68–74 (2003).

    Google Scholar 

  89. Ponticelli, C. Recurrence of focal segmental glomerular sclerosis after renal transplantation. Nephrol. Dial. Transplant. 25, 25–31 (2010).

    Article  PubMed  Google Scholar 

  90. Nozu, K. et al. Rituximab treatment for posttransplant lymphoproliferative disorder induces complete remission of recurrent nephrotic syndrome. Pediatr. Nephrol. 20, 1660–1663 (2005).

    Article  PubMed  Google Scholar 

  91. Sakai, K. et al. Protocol biopsies for focal segmental glomerulosclerosis treated with plasma exchange and rituximab in a renal transplant patient. Clin. Transplant. 24, 60–65 (2010).

    Article  PubMed  Google Scholar 

  92. Kumar, J. et al. Rituximab in post-transplant pediatric recurrent focal segmental glomerulosclerosis. Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467-012-2314-6.

  93. Tsagalis, G., Psimenou, E., Nakopoulou, L. & Laggouranis, A. Combination treatment with plasmapheresis and rituximab for recurrent focal segmental glomerulosclerosis after renal transplantation. Artif. Organs 35, 420–425 (2011).

    Article  PubMed  Google Scholar 

  94. Stewart, Z. A., Shetty, R., Nair, R., Reed, A. I. & Brophy, P. D. Case report: successful treatment of recurrent focal segmental glomerulosclerosis with a novel rituximab regimen. Transplant. Proc. 43, 3994–3996 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Gossmann, J. et al. Abrogation of nephrotic proteinuria by rituximab treatment in a renal transplant patient with relapsed focal segmental glomerulosclerosis. Transpl. Int. 20, 558–562 (2007).

    Article  PubMed  Google Scholar 

  96. Grenda, R., Jarmuz˙ek, W., Pia˛to sa, B. & Rubik, J. Long-term effect of rituximab in maintaining remission of recurrent and plasmapheresis-dependent nephrotic syndrome post-renal transplantation-case report. Pediatr. Transplant. 15, e121–e125 (2011).

    Article  PubMed  Google Scholar 

  97. Audard, V. et al. Rituximab therapy prevents focal and segmental glomerulosclerosis recurrence after a second renal transplantation. Transpl. Int. 25, e62–e66 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Chikamoto, H. et al. Pretransplantation combined therapy with plasmapheresis and rituximab in a second living-related kidney transplant pediatric recipient with a very high risk for focal segmental glomerulosclerosis recurrence. Pediatr. Transplant. 16, e286–e290 (2012).

    Article  PubMed  Google Scholar 

  99. Gohh, R. Y. et al. Preemptive plasmapheresis and recurrence of FSGS in high-risk renal transplant recipients. Am. J. Transplant. 5, 2907–2912 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. McDonald, V., Manns, K., Mackie, I. J., Machin, S. J. & Scully, M. A. Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura. J. Thromb. Haemost. 8, 1201–1208 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Glassock, R. J. Diagnosis and natural course of membranous nephropathy. Semin. Nephrol. 3, 324–332 (2003).

    Article  Google Scholar 

  102. [No authors listed]. Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int. 13, 159–165 (1978).

  103. Beck, L. H. & Salant, D. J. Membranous nephropathy: recent travels and new roads ahead. Kidney Int. 77, 765–770 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Zeng, C. H. et al. Etiology and clinical characteristics of membranous nephropathy in Chinese patients. Am. J. Kidney Dis. 52, 691–698 (2008).

    Article  PubMed  Google Scholar 

  105. Polanco, N. et al. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J. Am. Soc. Nephrol. 21, 697–704 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schieppati, A. et al. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD004293. http://dx.doi.org/search/site/CD004293.

  107. Kidney Disease Improving Global Outcomes (KDIGO). Idiopathic membranous nephropathy. Kidney Int. Suppl. 2, 186–197 (2012).

  108. Cattran, D. C., Reich, H. N., Kim, S. J. & Troyanov, S. Have we changed the outcome in membranous nephropathy? A propensity study on the role of immunosuppressive therapy. Clin. J. Am. Soc. Nephrol. 6, 1591–1598 (2011).

    Article  PubMed  Google Scholar 

  109. Remuzzi, G. et al. Rituximab for idiopathic membranous nephropathy. Lancet 360, 923–924 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Beck, L. H. et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 361, 11–21 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Beck, L. H. Jr et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J. Am. Soc. Nephrol. 22, 1543–1550 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hofstra, J. M., Beck, L. H. Jr, Beck, D. M., Wetzels, J. F. & Salant, D. J. Antiphospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin. J. Am. Soc. Nephrol. 6, 1286–1291 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Stahl, R. A. K., Hoxha, E. & Fechner, K. PLA2R autoantibodies and recurrent membranous nephropathy after transplantation. N. Engl. J. Med. 363, 496–498 (2010).

    Article  PubMed  Google Scholar 

  114. Michel, P. A. et al. Rituximab treatment for membranous nephropathy: a French clinical and serological retrospective study of 28 patients. Nephron Extra 1, 251–261 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Murtas, C. et al. Co-existence of different circulating anti-podocyte antibodies in membranous nephropathy. Clin. J. Am. Soc. Nephrol. http://dx.doi.org/10.2215/CJN.02170312.

  116. Hoxha, E. et al. An immunofluorescence test for phospholipase-A2-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis. Nephrol. Dial. Transplant. 26, 2526–2532 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Bomback, A. S. et al. Rituximab therapy for membranous nephropathy: a systematic review. Clin. J. Am. Soc. Nephrol. 4, 734–744 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Segarra, A. et al. Successful treatment of membranous glomerulonephritis with rituximab in calcineurin inhibitor-dependent patients. Clin. J. Am. Soc. Nephrol. 4, 1083–1088 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sprangers, B. et al. Beneficial effect of rituximab in the treatment of recurrent idiopathic membranous nephropathy after kidney transplantation. Clin. J. Am. Soc. Nephrol. 5, 790–797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cravedi, P. et al. Efficacy and safety of rituximab second-line therapy for membranous nephropathy: a prospective, matched-cohort study. Am. J. Nephrol. 33, 461–468 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Ruggenenti, P. et al. Rituximab in idiopathic membranous glomerulonephritis, J. Am. Soc. Nephrol. 23, 1416–1425 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Rodriguez, E. F. et al. The pathology and clinical features of early recurrent membranous glomerulonephritis. Am. J. Transplant. 12, 1029–1038 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Ruggenenti, P. et al. Rituximab for idiopathic membranous nephropathy: who can benefit? Clin. J. Am. Soc. Nephrol. 1, 738–748 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Irazabal, M. V. et al. Low- and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: a prospective study. Nephrol. Dial. Transplant. http://dx.doi.org/10.1093/ndt/gfs379.

  125. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  126. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  127. Ardelean, D. S. et al. Severe ulcerative colitis after rituximab therapy. Pediatrics 126, e243–e246 (2010).

    Article  PubMed  Google Scholar 

  128. Strologo, D. L. et al. Use of rituximab in focal glomerulosclerosis relapses after renal transplantation. Transplantation 88, 417–420 (2009).

    Article  CAS  Google Scholar 

  129. Atmar, J. Review of the safety and feasibility of rapid infusion of rituximab. J. Oncol. Practice 6, 91–93 (2010).

    Article  Google Scholar 

  130. Kamar, N. et al. Treatment of focal segmental glomerular sclerosis with rituximab: 2 case reports. Clin. Nephrol. 67, 250–254 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Bayrakci, U. S., Baskin, E., Sakalli, H., Karakayali, H. & Haberal, M. Rituximab for post-transplant recurrences of FSGS. Pediatr. Transplant. 13, 240–243 (2009).

    Article  PubMed  Google Scholar 

  132. Thevenin, C., Lucas, B. P., Kozlow, E. J. & Kehrl, J. H. Cell type- and stage-specific expression of the CD20/B1 antigen correlates with the activity of a diverged octamer DNA motif present in its promoter. J. Biol. Chem. 268, 5949–5956 (1993).

    CAS  PubMed  Google Scholar 

  133. Lim, S. H. et al. B-cell depletion for 2 years after autologous stem cell transplant for NHL induces prolonged hypogammaglobulinemia beyond the rituximab maintenance period. Leuk. Lymphoma 49, 152–153 (2008).

    Article  PubMed  Google Scholar 

  134. Wang, Q. S. et al. Change of serum immunoglobulin level in patients with diffuse large B cell lymphoma after rituximab combined with chemotherapy [Chinese]. Zhongguo Shi Yan Xue Ye Za Zhi 19, 676–679 (2011).

    CAS  Google Scholar 

  135. Cooper, N., Davies, E. G. & Thrasher, A. J. Repeated course of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin. Br. J. Haematol. 146, 120–122 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Lee, Y. H., Bae, S. C. & Song, G. G. The efficacy and safety of rituximab for the treatment of active rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. Rheumatol. Int. 31, 1493–1499 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Lanini, S. et al. Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis. BMC Med. 9, 36 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Vidal, L. et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials. J. Natl Cancer Inst. 103, 1799–1806 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Aksoy, S., Dizdar, O., Hayran, M. & Harputluog˘lu, H. Infectious complications of rituximab in patients with lymphoma during maintenance therapy: a systematic review and meta-analysis. Leuk. Lymphoma 50, 357–365 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Sato, M. et al. Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome. Pediatr. Nephrol. 1, 145–149 (2013).

    Article  Google Scholar 

  141. Teichmann, L. L. et al. Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology (Oxford) 47, 1256–1257 (2008).

    Article  CAS  Google Scholar 

  142. Podolskaya, A., Stadermann, M., Pilkington, C., Marks, S. D. & Tullus, K. B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch. Dis. Child. 93, 401–406 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Kahwaji, J. et al. Infectious complications in kidney-transplant recipients desensitized with rituximab and intravenous immunoglobulin. Clin. J. Am. Soc. Nephrol. 6, 2894–2900 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kamar, N. et al. Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients. Am. J. Transplant. 10, 89–98 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Tsutsumi, Y. et al. Rituximab administration and reactivation of, H. B. V. Hepat. Res. Treat. http://dx.doi.org/10.1155/2010/182067.

  146. Mastroianni, C. M. et al. Current trends in management of hepatitis B virus reactivation in the biologic therapy era. World J. Gastroenterol. 17, 3881–3887 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Bennett, C. L. Pharmacovigilance and PML in the oncology setting. Clin. J. Med. 78 (Suppl. 2), S13–S17 (2011).

    Google Scholar 

  148. US Food and Drug Administration. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Rituxan (rituximab)–PML [online], (2012).

  149. Delbue, S. et al. Investigation of polyomaviruses replication in pediatric patients with nephropathy receiving rituximab. J. Med. Virol. 84, 1464–1470 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Herishanu, Y. et al. Fatal interstitial pneumonitis related to rituximab-containing regimen. Clin. Lymphoma Myeloma 6, 407–409 (2006).

    Article  PubMed  Google Scholar 

  151. Hadjinicolaou, A. V., Nisar, M. K., Parfrey, H., Chilvers, E. R. & Ostor, A. J. Non-infectious pulmonary toxicity of rituximab: a systematic review. Rheumatology (Oxford) 51, 653–662 (2012).

    Article  CAS  Google Scholar 

  152. Bitzan, M., Anselmo, M. & Carpineta, L. Rituximab (B-cell depleting antibody) associated lung injury (RALI): pediatric case and systematic review of the literature. Pediatr. Pulmonol. 44, 922–934 (2009).

    Article  PubMed  Google Scholar 

  153. Chaumais, M. et al. Fatal pulmonary fibrosis after rituximab administration. Pediatr. Nephrol. 24, 1753–1755 (2009).

    Article  PubMed  Google Scholar 

  154. Ergin, A. B., Fong, N. & Daw, H. A. Rituximab-induced bronchiolitis obliterans organizing pneumonia. Case Reports Med. http://dx.doi.org/10.1155/2012/680431.

  155. Albert, D. et al. Variability in the biological response to anti-CD20 B-cell depletion in systemic lupus erythematosus. Ann. Rheum. Dis. 67, 1724–1731 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. Igarashi, T. et al. Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study. Ann. Oncol. 13, 928–943 (2002).

    Article  CAS  PubMed  Google Scholar 

  157. Lunardon, L. & Payne, A. S. Inhibitory human antichimeric antibodies to rituximab in a patient with pemphigus. J. Allergy Clin. Immunol. 130, 800–803 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Looney, R. J. et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. 50, 2580–2589 (2004).

    Article  CAS  PubMed  Google Scholar 

  159. Davis, T. A. et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J. Clin. Oncol. 18, 3135–3143 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Robak, T. & Robak, E. New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies. BioDrugs 25, 13–25 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the All India Institute of Medical Sciences, New Delhi, for supporting their research.

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  1. Division of Nephrology, Department of Paediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Aditi Sinha & Arvind Bagga

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  1. Aditi Sinha
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  2. Arvind Bagga
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A. Sinha and A. Bagga contributed equally to researching data for the manuscript, writing, discussions of the content, review and/or editing of the manuscript before submission.

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Correspondence to Arvind Bagga.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Box 1

Suggestions for future clinical studies (DOC 34 kb)

Supplementary Figure 1

Rates of remission after rituximab therapy in patients with idiopathic membranous nephropathy. (PDF 36 kb)

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Sinha, A., Bagga, A. Rituximab therapy in nephrotic syndrome: implications for patients' management. Nat Rev Nephrol 9, 154–169 (2013). https://doi.org/10.1038/nrneph.2012.289

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